Depression is one of the most frequent psychological problems. In France, the proportion of depressive people is 14.9%, including one third of whom are not treated medically. One woman out of five is affected. The prevalence of declared depression has increased by a factor of 6 since 1970. The proportion of depressive persons increased between 1992 and 1997, particularly among the young from 20 to 29 years old (+65%). Therefore, it is particularly important to find treatments better adapted to depression, particularly since some patients may not respond to classical antidepressants.
Derivatives of 20,21-dinoreburnamenin, including 14,15-dihydro 20,21-dinoreburnamenin14-ol, are already known for their vaso-expanding properties, particularly cerebral, and for their activity in regulation of tyrosine hydroxylase in the locus coeruleus (Bourde et al., Neurochem. Int., 23 (6), 567-574, 1993). They are used for cerebral vasculopathies and for all syndromes caused by alteration of cerebral circulation. These derivatives and their first known therapeutic application were described in patent application FR 2 381 048, published on Sep. 15, 1978. This patent application was described in the additive certificate application FR 2 433 528 published on Mar. 14, 1980.
More particularly, application FR 2 381 048 describes derivatives of 20,21-dinoreburnamenin and their preparation process. The pharmacological properties of these compounds are also described: these compounds are valuable cerebral oxygenators and vasoregulators that in particular increase cerebral flow in the cerebral microcirculation. Application FR 2 433 528 also describes the process for preparation of a particular isomer derived from 20,21-dinorebumamenin, and the isomer obtained by this process.
Application WO 89/04830, published on Jun. 1, 1989, describes new substitute derivatives of 20,21-dinoreburnamenin, the process for their preparation and their application as a medicine particularly as an antidepressant.
Depression is a pathological psychic condition combining a stressful mood change and slowing of intellectual activity and motricity. It is a morbid condition, more or less long term, characterised by a certain sadness and reduction of the energy tonicity. A bipolar depression is characterised by alternating phases: marked dejection and inertia in the first phase, euphoria and hyperactivity in the second phase.
The main symptoms used to diagnose depression in a person are depressive mood, marked reduction of interest or pleasure, problems in feeding, sleep problems, agitation or slowed psychomotricity, tiredness or loss of energy, lack of self-esteem, or an excessive feeling of culpability, a reduction of the ability to think or concentrate, or uncertainty, morbid thoughts (60% of cases) suicidal thoughts (in 15% of cases).
Causes of depression include:
1/ The Hereditary Factor
Persons whose close relatives suffer from or have suffered from depression are most likely to be affected. They have a 15% risk of developing depression, while persons whose close relatives are not depressive only have 2 to 3% risk of developing a depression.
2/ The Biochemical Factor
Current research on depression applies to neurotransmitters. It has thus been noticed that a serotonin deficiency or unbalance caused sleep loss and reduced appetite, and also that a reduction in noradrenalin has an effect on loss of energy, loss of pleasure.
3/ Environmental Factors
Children who have experienced the loss of a loved one such as their parents are more likely to develop depression later in their life. Difficulties in relations, communication problems and family, professional or other conflicts may also contribute to solitude, alienation and result in depression. Financial difficulties and other tensions can also have an important impact.
Seasonal factors must not be neglected: the depression rate is higher during months in which sunshine is lowest. Seasonal depression only occurs during the period of the year during which days are shortest, thus it occurs in winter and disappears in spring. Symptoms include tiredness, dejection, lack of vitality and loss of interest, problems with concentration and libido, sudden desire for anything sweet, an increased need for sleep or increased weight during the winter. This is what is sometimes called winter depression. 2% of all adults in central Europe are affected by seasonal depression and women are affected 4 times more frequently than men.
Depression is often accompanied by other psychological problems or it may accompany another psychological problem. Acute panic attacks and obsessions are the most frequent problems.
Schizophrenia is a chronic psychosis characterised by psychic dissociation or a discordance that disturbs the course of thought (it becomes hermetic and chaotic), it changes behaviour (which becomes strange, autistic) and upsets affectivity (archaic and paradoxical), associated with an abstract and symbolic delirium that creates themes of influence fed by auditory and cenesthesic hallucinations, and experienced in a depersonalisation atmosphere.
Maniac-depressive diseases (bipolar depression) and schizophrenia, which are two mental diseases, have the same genetic origin: the expression of various genes involved in some brain cells and in the placement of the myelin (that propagates electrical signals) would be reduced. Although these two diseases have a different clinical progress, they share some symptoms and similar medicines are often used to treat them.
Currently there are two main types of treatment for depression and schizophrenia: treatment by medicine and psychotherapies. Treatment by medicines that consists of using antidepressants, is appropriate in all forms of depression. Antidepressants act on the equilibrium of neurotransmitters. Psychotherapies are helpful for patients, but cannot be the only treatment. There are other forms of treatments such as behavioural and cognitive therapies (particularly for neurotic depression), sismotherapy or electroshock (used as a last resort).
The progress of depression is very variable and depends on many parameters: etiology, personality of the patient, etc.
If no treatment is given, it often arises that a depression can last 6 months or more, occasionally ending in the extreme termination of suicide. Up to 15% of patients with a serious depression disorder commit suicide. A relapse is observed in about 60% of all cases after treatment.
Depression may be diagnosed using the DSM IV criteria (Diagnostic and Statistical Manual of Mental Disorders, 4th edition, American Psychiatric Association Publisher; Washington D.C.)); the DSM IV is a diagnostic and statistical baseline for mental disorders, produced by the American Psychiatry Association. According to the DSM IV criteria, severe depression that is the severe and most common form of depression and for which only 10 to 25% of patients search for treatment, is characterised by one or several episodes of mood change or loss of interest for at least two weeks accompanied by at least four additional symptoms of depression; these symptoms may for example be a change in appetite, weight, sleep or psychomotricity activity; reduction of energy, a feeling of reduced self-esteem, or culpability, difficulty in thinking, concentrating, making decisions, or recurrent thoughts of death, or ideation of plans or attempts to commit suicide.
Major depressions include Treatment Resistant Depressions (TRD), and also Major Recurrent Depressive Disorders (MRDD), that are associated with hypomaniac episodes.
Classical antidepressants currently and frequently marketed belong to the following main classes: tricyclic antidepressants (TCA), monoamine oxidase inhibitors (MAO) (MAOIs), selective serotonin recapture inhibitors (SSRIs), serotonin and noradrenalin recapture inhibitors (SNDRIs), noradrenalin and selective serotonin antidepressants (NASSAs) and serotonin receptor modulators.
There is still a need for compounds capable of treating depression and/or major depression disorders in a patient who may be resistant to a treatment using the classical antidepressants mentioned above.